It is well known that substances in the saliva of Phlebotomine sand flies enhance pathogenesis of leishmanial parasites in their mammalian hosts and exacerbates the pathology these parasites produce. These findings have had a profound effect on our understanding of the relationship between insect vectors, the parasites they transmit, and the diseases they cause. However, major gaps in our knowledge of this relationship remain. All studies to date aimed at exploring the effects of sand fly saliva have examined its effects on cutaneous leishmaniasis. In this proposal we aim to examine the affects of the saliva of Lutzomyia longipalpis on the development of visceral disease caused by Leishmania chagasi. We will examine the influence of vector saliva and specific salivary proteins on the visceralization of this parasite in hamsters. L. chagasi is known to cause only visceral leishmaniasis in South America, however in Central America, the identical parasite, transmitted by the same vector species, causes a benign atypical cutaneous disease. We have shown that Lu. longipalpis in Central America differ dramatically in the amount of the salivary protein known as maxadilan contained in their saliva as compared to Lu. longipalpis in South America. We have developed a highly efficient system for infecting this sand fly with L. chagasi and transmitting this parasite to hamsters via sand fly bite. These hamsters go on to develop visceral leishmaniasis. We present data showing that when we transmit L. chagasi to hamsters via the bite of Lu. longipalpis from Brazil they develop heavy infections in the liver and spleen, whereas when the same parasite strain is transmitted by flies from Costa Rica the hamsters for the most part fail to develop liver or spleen infections or if they do these infections are light. We propose to study the affect of sand fly saliva on visceralization of L. chagasi through 3 specific aims. In Aim #1 we will conduct a detailed analysis of the pathology of L. chagasi in hamsters infected via the bite of flies from the Costa Rican and Brazilian strains. In Aim #2 we will determine if immunization with salivary gland extract or synthetic maxadilan will protect hamsters from developing visceral disease. Finally, in Aim #3, we will evaluate the immunomodulatory properties of maxadilan variants found in natural populations of Lu. longipalpis from Brazil and Costa Rica.